JP6862464B2 - Faecalibacterium longum and its use - Google Patents
Faecalibacterium longum and its use Download PDFInfo
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- JP6862464B2 JP6862464B2 JP2018546802A JP2018546802A JP6862464B2 JP 6862464 B2 JP6862464 B2 JP 6862464B2 JP 2018546802 A JP2018546802 A JP 2018546802A JP 2018546802 A JP2018546802 A JP 2018546802A JP 6862464 B2 JP6862464 B2 JP 6862464B2
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- longum
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- faecalibacterium
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Description
本発明は、微生物学の分野に属し、具体的に、糖尿病およびその関連疾患の治療と予防におけるフィーカリバクテリウム・ロンガム(Faecalibacterium longum)の使用、そして、フィーカリバクテリウム・ロンガムを含む組成物およびその使用に関する。 The present invention belongs to the field of microbiology, specifically the use of Faecalibacterium longum in the treatment and prevention of diabetes and related diseases, and compositions comprising Faecalibacterium longum. And its use.
人体の腸内に大量の共生微生物が棲み、これらの共生微生物群で人体の「第二の器官」を構成し、宿主と協同で栄養物質の消化と吸収に関与するだけでなく、人体の健康の維持に重要な役割を果たす。細胞数からすると、腸内微生物のすべての細胞の数は人体の細胞数の数十倍で、これらの巨大な微生物群は主にファーミキューテス門とバクテロイデス門との2種類からなる。腸内微生物の組成および多様性は、たとえば、肥満、糖尿病、過敏性腸症候群、潰瘍性腸炎、結腸癌、脂肪肝などの多くの疾患の発生に密接に関連することを示す研究が増えてきた。環境、飲食、薬物などの影響によって、元の健康状態における腸内微生物のバランスが崩れ、腸管機能障害が生じ、さらに以上の疾患の発生につながる。 A large number of symbiotic microorganisms live in the intestines of the human body, and these symbiotic microorganisms form the "second organ" of the human body, and not only participate in the digestion and absorption of nutrients in cooperation with the host, but also the health of the human body. Plays an important role in maintaining the. In terms of the number of cells, the number of all cells of gut microbiota is several tens of times the number of cells of the human body, and these huge microbial groups consist mainly of two types, Firmicutes and Bacteroidetes. Increasing studies have shown that the composition and diversity of gut microbiota is closely associated with the development of many diseases, such as obesity, diabetes, irritable bowel syndrome, ulcerative colitis, colon cancer, and fatty liver. .. Due to the influence of the environment, eating and drinking, drugs, etc., the balance of intestinal microorganisms in the original health state is disturbed, intestinal dysfunction occurs, and further diseases occur.
近年、人々の日常生活のレベルの向上とともに、飲食の構成はだんだんバランスが取れなくなり、肥満、糖尿病などの代謝性疾患の発症率が急速に上がってきた。世界保険機関の統計によると、2014年に全世界で約4.22億人が糖尿病に罹り、2012年までに、糖尿病による死亡者数が150万人に達したという。そのため、糖尿病は次なる深刻な公共健康問題になっている。糖尿病は多くの要素による血糖が異常に過剰上昇する疾患で、主にインスリンの分泌不足またはインスリンの機能欠陥による代謝性障害で、糖尿病の発症を引き起こすよく見られるハイリスク要因には遺伝要素、環境要素および良くない生活習慣がある。糖尿病の発生に伴い、多くの合併症、たとえば、冠動脈性心疾患、高血圧、心筋梗塞、脳卒中、認知症、パーキンソン病、腎臓疾患、網膜疾患などが現れ、患者の生活品質を大幅に低下させる。中でも、2型糖尿病はインスリン非依存型糖尿病で、罹患者数はすべての糖尿病患者の数の90%を占めている。大量の研究で、2型糖尿病の発症は腸内細菌叢の乱れと密接に関連し、腸内細菌叢は宿主との間でエネルギーのバランスおよび炎症反応の調節と密接に関連し、2型糖尿病の発症は主にインスリン抵抗性および低レベルの炎症反応によるものである。
In recent years, as the level of daily life of people has improved, the composition of food and drink has become increasingly unbalanced, and the incidence of metabolic diseases such as obesity and diabetes has rapidly increased. According to statistics from the World Insurance Agency, about 422 million people worldwide suffered from diabetes in 2014, and by 2012, the death toll from diabetes had reached 1.5 million. As a result, diabetes has become the next serious public health problem. Diabetes is a disease in which blood sugar is abnormally excessively elevated due to many factors, mainly due to insufficient insulin secretion or metabolic disorders due to insulin dysfunction, and genetic factors and environment are common high-risk factors that cause the onset of diabetes. There are elements and bad lifestyles. With the development of diabetes, many complications such as coronary heart disease, hypertension, myocardial infarction, stroke, dementia, Parkinson's disease, kidney disease, retinal disease, etc. appear, and the quality of life of the patient is significantly reduced. Among them,
現在、糖尿病を治療するための血糖降下薬はスルホニルウレア類、α-グルコシダーゼ阻害薬、ビグアナイド類がある。中では、スルホニルウレア類は主にインスリンの分泌を促進するが、深刻な肝臓、腎臓の損傷を起こし、かつアレルギー体質の人への投与は好適ではない。α-グルコシダーゼ阻害薬は主にα-アミラーゼと腸内におけるα-グルコシダーゼの活性と抑制し、炭水化物の加水分解を抑制することによって、食後の血糖を抑えるという目的を実現するが、腹部膨満、下痢などの有害反応が生じやすい。ビグアナイド類薬物は血糖の輸送の調節、たとえば糖吸収の遅延、ブドウ糖の分解の促進、肝臓でのブドウ糖の生成の抑制、グルコーストランスポーター量の増加によって血糖を低下させる目的を果たすことができる。ビグアナイド類薬物はある程度の副作用ももたらし、胃腸不快、下痢、嘔吐、皮疹が生じやすく、長期間投与すると不活性化しがちである。 Currently, hypoglycemic agents for treating diabetes include sulfonylureas, α-glucosidase inhibitors, and biguanides. Among them, sulfonylureas mainly promote insulin secretion, but they cause serious liver and kidney damage and are not suitable for administration to people with allergies. α-Glucosidase inhibitors mainly achieve the purpose of suppressing postprandial blood glucose by suppressing the activity of α-amylase and α-glucosidase in the intestine and suppressing the hydrolysis of carbohydrates, but abdominal distension and diarrhea. Such adverse reactions are likely to occur. Biguanide drugs can serve the purpose of lowering blood glucose by regulating blood glucose transport, such as delaying glucose absorption, promoting glucose breakdown, suppressing glucose production in the liver, and increasing glucose transporter levels. Biguanide drugs also cause some side effects, are prone to gastrointestinal discomfort, diarrhea, vomiting, and rash, and tend to be inactivated after long-term administration.
そのため、本分野では、毒性・副作用のない、糖尿病およびその関連疾患の治療と予防のための新規な薬物の開発が切望されている。 Therefore, in this field, the development of new drugs for the treatment and prevention of diabetes and related diseases without toxicity and side effects is eagerly desired.
本発明のもう一つの目的は、糖尿およびその関連疾患の治療と予防におけるフィーカリバクテリウム・ロンガムの使用を提供することである。 Another object of the present invention is to provide the use of Phycaribacterium longum in the treatment and prevention of diabetes and related diseases.
本発明のもう一つの目的は、有効で毒性・副作用のない、糖尿病およびその関連疾患の治療と予防のための薬品、飲料、食品組成物、または動物飼料組成物を提供することである。 Another object of the present invention is to provide a drug, beverage, food composition, or animal feed composition for the treatment and prevention of diabetes and related diseases, which is effective and has no toxicity or side effects.
本発明のもう一つの目的は、体重、空腹時血糖および/または血中脂質を低下させる方法およびその使用を提供することである。 Another object of the present invention is to provide a method and use thereof for lowering body weight, fasting blood glucose and / or blood lipids.
本発明のもう一つの目的は、耐糖能を向上させる方法およびその使用を提供することである。 Another object of the present invention is to provide a method for improving glucose tolerance and its use.
本発明の第一の側面では、Faecalibacterium longumであるフィーカリバクテリウム・ロンガムを提供する。 A first aspect of the present invention provides Faecalibacterium longum, Faecalibacterium longum.
もう一つの好適な例において、前記のフィーカリバクテリウム・ロンガムの16s rDNAの配列は、配列番号1で示されるものである。 In another preferred example, the 16s rDNA sequence of the Ficalibacterium longum described above is that shown in SEQ ID NO: 1.
もう一つの好適な例において、前記フィーカリバクテリウム・ロンガムはFaecalibacterium longum CM04-06で、寄託番号はCGMCC 1.5208である。 In another preferred example, the Faecalibacterium longum is Faecalibacterium longum CM04-06 and the deposit number is CGMCC 1.5208.
本発明の第二の側面では、(a)安全有効量の請求項1に記載のフィーカリバクテリウム・ロンガムおよび/またはその代謝産物と、(b)食品的に許容される担体または薬学的に許容される担体とを含む組成物を提供する。
In the second aspect of the present invention, (a) a safe and effective amount of the phicalibacterium longum and / or its metabolite according to
もう一つの好適な例において、前記組成物はさらに牛乳成長因子を含む。 In another preferred example, the composition further comprises milk growth factor.
もう一つの好適な例において、前記組成物は、食品組成物、保健組成物、薬物組成物、飲料組成物、飼料組成物、またはこれらの組み合わせからなる群から選ばれる。 In another preferred example, the composition is selected from the group consisting of food compositions, health compositions, drug compositions, beverage compositions, feed compositions, or combinations thereof.
もう一つの好適な例において、前記の組成物は経口投与製剤である。 In another preferred example, the composition is an orally administered formulation.
もう一つの好適な例において、前記の組成物は液体製剤、固体製剤、半固体製剤である。 In another preferred example, the composition is a liquid formulation, a solid formulation, a semi-solid formulation.
もう一つの好適な例において、前記の組成物の剤形は、粉末剤、散剤、錠剤、糖衣剤錠剤、カプセル剤、顆粒剤、懸濁剤、溶液剤、シロップ剤、ドロップ剤、およびトローチ剤からなる群から選ばれる。 In another preferred example, the dosage forms of the above compositions are powders, powders, tablets, sugar-coated tablets, capsules, granules, suspensions, solutions, syrups, drops, and lozenges. Selected from the group consisting of.
もう一つの好適な例において、前記の食品組成物は、乳液製品、溶液製品、粉末製品、または懸濁液製品を含む。 In another preferred example, the food composition comprises an emulsion product, a solution product, a powder product, or a suspension product.
もう一つの好適な例において、前記の食品組成物は、乳製品、粉乳、または液体乳を含む。 In another preferred example, the food composition comprises a dairy product, milk powder, or liquid milk.
もう一つの好適な例において、前記の液体製剤は、溶液製品または懸濁液製品からなる群から選ばれる。 In another preferred example, the liquid formulation is selected from the group consisting of solution products or suspension products.
もう一つの好適な例において、前記組成物は、前記組成物の全体積または全重量に対し、1×10〜1×1010 cfu/mLまたはcfu/gのFaecalibacterium longum CM04-06を、好ましくは1×104〜1×1010cfu/mLまたはcfu/gのFaecalibacterium longum CM04-06を含有する。 In another preferred example, the composition is 1 × 10 to 1 × 10 10 cfu / mL or cfu / g of Faecalibacterium longum CM04-06, preferably with respect to the total volume or weight of the composition. Contains 1 × 10 4 to 1 × 10 10 cfu / mL or cfu / g of Faecalibacterium longum CM04-06.
もう一つの好適な例において、前記の組成物に、前記組成物の全重量に対し、0.0001〜99wt%、好ましくは0.1〜90wt%の前記のフィーカリバクテリウム・ロンガムおよび/またはその代謝産物が含有される。 In another preferred example, the composition comprises 0.0001-99 wt%, preferably 0.1-90 wt% of the Phycaribacterium longum and / or its metabolites based on the total weight of the composition. It is contained.
もう一つの好適な例において、前記の生成物は、単位剤形(1錠、1カプセルまたは1小瓶)で、1単位剤形あたりの質量は0.05〜5gで、好ましくは0.1〜1gである。 In another preferred example, the product is in a unit dosage form (1 tablet, 1 capsule or 1 vial) with a mass of 0.05-5 g, preferably 0.1-1 g per unit dosage form.
もう一つの好適な例において、前記の組成物は、さらに、ほかのプロバイオティクスおよび/またはプレバイオティクスを含有する。 In another preferred example, the composition further comprises other probiotics and / or prebiotics.
もう一つの好適な例において、前記のプロバイオティクスは、乳酸菌、ビフィドバクテリウム、ラクトバチルス・アシドフィルス、またはこれらの組み合せからなる群から選ばれる。 In another preferred example, the probiotics are selected from the group consisting of lactic acid bacteria, bifidobacteria, Lactobacillus acidophilus, or a combination thereof.
もう一つの好適な例において、前記のプレバイオティクスは、フラクトオリゴ糖(FOS)、ガラクトオリゴ糖(GOS)、キシロオリゴ糖(XOS)、乳果オリゴ糖(LACT)、大豆オリゴ糖(SOS)、イヌリン(Inulin)、またはこれらの組み合せからなる群から選ばれる。 In another preferred example, the prebiotics are fructooligosaccharide (FOS), galactooligosaccharide (GOS), xylooligosaccharide (XOS), milk fruit oligosaccharide (LACT), soybean oligosaccharide (SOS), inulin ( Inulin), or a group of combinations of these.
本発明の第三の側面では、本発明の第一の側面に記載のフィーカリバクテリウム・ロンガム、または本発明の第二の側面に記載の組成物の使用であって、(a)肥満の予防および/または治療、(b)血中脂質の低下、(c)心血管疾患の予防または治療、ならびに/あるいは(d)糖尿病の予防および/または治療からなる群から選ばれる一つまたは複数の用途に使用される薬物または製剤の製造のための使用を提供する。 A third aspect of the invention is the use of the Phycaribacterium longum described in the first aspect of the invention, or the composition described in the second aspect of the invention, wherein (a) obesity. One or more selected from the group consisting of prevention and / or treatment, (b) reduction of blood lipids, (c) prevention or treatment of cardiovascular disease, and / or (d) prevention and / or treatment of diabetes. Provide use for the manufacture of a drug or formulation used in an application.
もう一つの好適な例において、前記製剤は、マイクロ生態製剤を含む。 In another preferred example, the formulation comprises a microecologic formulation.
本発明の第四の側面では、本発明の第一の側面に記載のフィーカリバクテリウム・ロンガム、または本発明の第二の側面に記載の組成物の使用であって、
(i)哺乳動物の体重増加の抑制、
(ii)哺乳動物の血中脂質レベルの低下、
(iii)哺乳動物における高密度リポタンパク質(HDL-C)のレベルの向上、
(iv)哺乳動物における低密度リポタンパク質(LDL-C)のレベルの低下、
(v)哺乳動物の血糖レベルの低下、
(vi)哺乳動物の耐糖能の向上、
からなる群から選ばれる一つまたは複数の用途に使用される薬物または製剤の製造のための使用を提供する。
In the fourth aspect of the present invention, there is the use of Phycaribacterium longum according to the first aspect of the present invention, or the composition according to the second aspect of the present invention.
(I) Suppression of mammalian weight gain,
(Ii) Decreased blood lipid levels in mammals,
(Iii) Increased levels of high-density lipoprotein (HDL-C) in mammals,
(Iv) Decreased levels of low-density lipoprotein (LDL-C) in mammals,
(V) Decreased blood glucose levels in mammals,
(Vi) Improvement of glucose tolerance in mammals,
Provided is the use for the manufacture of a drug or formulation used for one or more uses selected from the group consisting of.
もう一つの好適な例において、前記哺乳動物は、ヒト、齧歯動物(たとえばラット、マウス)を含む。 In another preferred example, the mammal comprises a human, a rodent (eg, rat, mouse).
もう一つの好適な例において、前記哺乳動物の血中脂質レベルの低下は、総コレステロール(TC)レベルおよび/またはトリグリセリドレベルの低下を含む。 In another preferred example, the reduction in blood lipid levels in the mammal comprises a reduction in total cholesterol (TC) levels and / or triglyceride levels.
もう一つの好適な例において、前記哺乳動物の血糖レベルの低下は、空腹時血糖レベルの低下を含む。 In another preferred example, the decrease in blood glucose level of the mammal comprises a decrease in fasting blood glucose level.
本発明の第五の側面では、本発明の第二に記載の組成物の製造方法であって、本発明の第一の側面に記載のフィーカリバクテリウム・ロンガムおよび/またはその代謝産物を、食品的に許容される担体または薬学的に許容される担体と混合することによって、本発明の第二に記載の組成物を形成させる工程を含む方法を提供する。 A fifth aspect of the present invention is the method for producing a composition according to the second aspect of the present invention, wherein the phicalibacterium longum and / or a metabolite thereof according to the first aspect of the present invention is used. Provided is a method comprising the step of forming the composition according to the second aspect of the present invention by mixing with a food-acceptable carrier or a pharmaceutically acceptable carrier.
もう一つの好適な例において、前記製造方法は、さらに、成長因子と混合する工程を含む。 In another preferred example, the production method further comprises mixing with growth factors.
もう一つの好適な例において、前記成長因子は牛乳成長因子である。 In another preferred example, the growth factor is milk growth factor.
もう一つの好適な例において、前記成長因子はビタミン類物質、プリン類物質、ピリミジン類物質、またはこれらの組み合わせからなる群から選ばれる。 In another preferred example, the growth factor is selected from the group consisting of vitamins, purines, pyrimidines, or combinations thereof.
もう一つの好適な例において、前記組成物は経口投与製剤である。 In another preferred example, the composition is an orally administered formulation.
本発明の第六の側面では、(a)適切な培養条件において、本発明の第一の側面に記載のフィーカリバクテリウム・ロンガムを培養することによって、培養産物を得る工程、(b)任意に、前記培養産物からフィーカリバクテリウム・ロンガムの菌体および/またはその代謝産物を分離する工程、ならびに(c)任意に、工程(b)で分離されたフィーカリバクテリウム・ロンガムの菌体および/またはその代謝産物を食品的に許容される担体または薬学的に許容される担体と混合することによって、組成物を製造する工程を含む生産方法を提供する。 In the sixth aspect of the present invention, (a) a step of obtaining a culture product by culturing the metabolite longum according to the first aspect of the present invention under appropriate culture conditions, (b) optional. In addition, a step of separating the cells of Ficalibacterium longum and / or its metabolite from the culture product, and (c) optionally, the cells of Ficalibacterium longum isolated in step (b). Providing a production method comprising the step of producing a composition by mixing and / or a metabolite thereof with a edible or pharmaceutically acceptable carrier.
もう一つの好適な例において、工程(c)の前に、分離されたフィーカリバクテリウム・ロンガムの菌体および/またはその代謝産物を成長因子と混合する工程を含む。 In another preferred example, step (c) involves mixing the isolated Phycaribacterium longum cells and / or metabolites thereof with growth factors.
もう一つの好適な例において、前記成長因子は牛乳成長因子である。 In another preferred example, the growth factor is milk growth factor.
もう一つの好適な例において、前記成長因子はビタミン類物質、プリン類物質、ピリミジン類物質、またはこれらの組み合わせからなる群から選ばれる。 In another preferred example, the growth factor is selected from the group consisting of vitamins, purines, pyrimidines, or combinations thereof.
本発明の第七の側面では、体重、空腹時血糖および/血中脂質を低下させる方法であって、前記対象に本発明の第一の側面に記載のフィーカリバクテリウム・ロンガムおよび/またはその代謝産物、あるいは本発明の第二の側面に記載の組成物を施用する方法を提供する。 A seventh aspect of the present invention is a method of reducing body weight, fasting blood glucose and / or blood lipids, wherein the subject is the Ficalibacterium longum and / or the method according to the first aspect of the present invention. Provided is a method of applying a metabolite or the composition according to the second aspect of the present invention.
もう一つの好適な例において、前記の施用は経口投与を含む。 In another preferred example, the application comprises oral administration.
もう一つの好適な例において、前記の施用の投与量は0.01〜5 g/50 kg体重/日、好ましくは0.1〜2 g/50 kg体重/日である。 In another preferred example, the dosage of the application is 0.01-5 g / 50 kg bw / day, preferably 0.1-2 g / 50 kg bw / day.
もう一つの好適な例において、前記の対象は、哺乳動物、たとえばヒトを含む。 In another preferred example, the subject comprises a mammal, such as a human.
本発明の第七の側面では、耐糖能を向上させる方法であって、前記対象に本発明の第一の側面に記載のフィーカリバクテリウム・ロンガムおよび/またはその代謝産物、あるいは本発明の第二の側面に記載の組成物を施用する方法を提供する。 A seventh aspect of the present invention is a method for improving glucose tolerance, wherein the subject is the Phycaribacterium longum and / or a metabolite thereof described in the first aspect of the present invention, or the first aspect of the present invention. Provided is a method of applying the composition according to the second aspect.
もう一つの好適な例において、前記の施用は経口投与を含む。 In another preferred example, the application comprises oral administration.
もう一つの好適な例において、前記の施用の投与量は0.01〜5 g/50 kg体重/日、好ましくは0.1〜2 g/50 kg体重/日である。 In another preferred example, the dosage of the application is 0.01-5 g / 50 kg bw / day, preferably 0.1-2 g / 50 kg bw / day.
もう一つの好適な例において、前記の対象は、哺乳動物、たとえばヒトを含む。 In another preferred example, the subject comprises a mammal, such as a human.
もちろん、本発明の範囲内において、本発明の上記の各技術特徴および下記(たとえば実施例)の具体的に記述された各技術特徴は互いに組合せ、新しい、または好適な技術方案を構成できることが理解される。紙数に限りがあるため、ここで逐一説明しない。 Of course, within the scope of the present invention, it is understood that the above-mentioned technical features of the present invention and the specifically described technical features below (for example, Examples) can be combined with each other to form a new or suitable technical plan. Will be done. Since the number of papers is limited, I will not explain it here one by one.
本発明者は、幅広く深く研究したところ、意外に、フィーカリバクテリウム・ロンガム(Faecalibacterium longum)が糖尿病およびその関連疾患(たとえば心血管疾患、肥満疾患)を予防および治療する作用を有し、フィーカリバクテリウム・ロンガムを含有する活性組成物を実験対象に投与して飼育したところ、当該組成物が体重の増加を抑制し、血中脂質を低下させ、空腹時血糖を低くし、耐糖能を向上させ、有効に糖尿病、心血管および肥満などの病症を軽減することができることを見出した。これに基づき、本発明を完成させた。 As a result of extensive and in-depth research, the present inventor has surprisingly found that Faecalibacterium longum has the effect of preventing and treating diabetes and related diseases (for example, cardiovascular disease and obesity disease). When an active composition containing calibacterium longum was administered to an experimental subject and bred, the composition suppressed weight gain, lowered blood lipids, lowered fasting blood glucose, and improved glucose tolerance. It has been found that it can be improved and effectively alleviated diseases such as diabetes, cardiovascular and obesity. Based on this, the present invention has been completed.
本明細書で用いられるように、用語「含有」は、各種の成分が一緒に本発明の混合物または組成物に使用することができることを表す。そのため、用語「主に〜からなる」および「〜からなる」は、用語「含有」に含まれる。 As used herein, the term "contains" means that various ingredients can be used together in a mixture or composition of the present invention. Therefore, the terms "mainly composed of" and "consisting of" are included in the term "contains".
本明細書で用いられるように、用語「成長因子」、「牛乳成長因子」は入れ替えて使用することができ、いずれもビタミン類物質、プリン類物質、ピリミジン類物質、またはこれらの組み合わせの栄養物質である。 As used herein, the terms "growth factor" and "milk growth factor" can be interchanged and are all nutritional substances such as vitamins, purines, pyrimidines, or combinations thereof. Is.
ここで、前記ビタミン類物質は、ビタミンC、ビタミンE、ビタミンA、ビタミンA前駆体、ビタミンB6、ビタミンD3、ビタミンK、葉酸、またはこれらの組み合わせを含むが、これらに限定されない。 Here, the vitamin substances include, but are not limited to, vitamin C, vitamin E, vitamin A, vitamin A precursor, vitamin B 6 , vitamin D 3 , vitamin K, folic acid, or a combination thereof.
前記プリン類物質はプリンリボシドを含むが、これらに限定されず、ここで、前記プリンリボシドはプリンリボシドの5'-リン酸エステルを含み、前記プリンリボシドの5'-リン酸エステルは、イノシン酸(イノシン-5'-リン酸:IMP)、グアニル酸(グアノシン-5'-リン酸:GMP)、キサンチル酸(キサントシン-5'-リン酸:XMP)、アデニル酸(アデノシン-5'-リン酸:AMP)、またはこれらの組み合わせからなる群から選ばれる。 The purine substances include, but are not limited to, purinribosides, wherein the purinriboside comprises a 5'-phosphate ester of purinriboside, and the 5'-phosphate ester of the purinriboside is inosinic acid (inosin-5). '-Phosphate: IMP), guanylic acid (guanosine-5'-phosphate: GMP), xanthylic acid (xanthosine-5'-phosphate: XMP), adenylic acid (anosin-5'-phosphate: AMP), Or it is selected from the group consisting of these combinations.
前記ピリミジン類物質は、すべてのピリミジン構造を含有する物質を含む。 The pyrimidine substances include substances containing all pyrimidine structures.
フィーカリバクテリウム・ロンガムおよびその使用
本明細書で用いられるように、用語「フィーカリバクテリウム・ロンガム」、「Faecalibacterium longum」は入れ替えて使用することができる。一つの好適な例において、前記菌株はFaecalibacterium longum CM04-06で、寄託番号はCGMCC 1.5208で、ヒトの糞便から分離されたものである。フィーカリバクテリウム・ロンガムの生理的特性は以下の通りである。フィーカリバクテリウム・ロンガムは嫌気環境において37℃で2〜3日培養した後、集落が黄白色で、含水量が高く、すこし粘稠で、ほぼ円形で、不透明で、平たくて中央が突起し、集落の直径が約2〜3mmである。グラム染色、顕微観察を行ったところ、CM04-06の菌体は長桿状で、グラム染色の反応は陰性で、芽胞と鞭毛が見られず、菌体の直径が約1μmで、長さが4〜10μmである。そして、本発明に記載のフィーカリバクテリウム・ロンガムはオキシダーゼおよびカタラーゼ反応がいずれも陰性で、生長温度の範囲が30〜45℃で、pH値の範囲が4.0〜9.0で、最適の温度およびpH値が37℃およびpH 7.0である。3%のNaClに耐えることができる。マンノース、ラフィノース、トレハロースを含むいくつかの炭水化物を発酵させることができ、主にギ酸、酢酸、酪酸、乳酸を生成し、また発酵によって菌体外多糖を生成することができる。
Faecalibacterium longum and its use As used herein, the terms "Faecalibacterium longum" and "Faecalibacterium longum" may be used interchangeably. In one preferred example, the strain is Faecalibacterium longum CM04-06 and the deposit number is CGMCC 1.5208, isolated from human feces. The physiological characteristics of Phycaribacterium longum are as follows. Phycaribacterium longum is cultivated in an anaerobic environment at 37 ° C for 2-3 days, after which the colony is yellowish white, has a high water content, is slightly viscous, almost round, opaque, flat and has a protruding center. , The diameter of the village is about 2-3 mm. Gram stain and microscopic observation revealed that the cells of CM04-06 were long rod-shaped, the reaction of Gram stain was negative, no spores and flagella were observed, the diameter of the cells was about 1 μm, and the length was 4. It is ~ 10 μm. The Phycaribacterium longum described in the present invention is negative for both oxidase and catalase reactions, has a growth temperature range of 30 to 45 ° C., a pH value range of 4.0 to 9.0, and an optimum temperature and pH. Values are 37 ° C and pH 7.0. Can withstand 3% NaCl. Several carbohydrates, including mannose, raffinose, and trehalose, can be fermented to produce mainly formic acid, acetic acid, butyric acid, and lactic acid, and fermentation can produce extracellular polysaccharides.
本発明は、糖尿病およびその関連疾患(たとえば心血管疾患、肥満疾患)の治療と予防におけるフィーカリバクテリウム・ロンガムの使用を提供する。高脂肪の食物を摂取する被験者において、菌株Faecalibacterium longum CM04-06は(i)当該被験者の体重増加の抑制、(ii)血中脂質の低下、(iii)空腹時血糖レベルの低下、(iv)耐糖能の向上からなる群から選ばれる一つまたは複数の用途を有する。本発明の一つの好適な例によれば、C57bL/6マウスを試験マウスとし、高脂肪飼料の投与およびストレプトゾトシン(STZ)の注射で誘導することによって、2型糖尿病(T2D)モデルマウスを得、菌株Faecalibacterium longum CM04-06で治療されたT2Dモデルマウスは、治療を受けなかった対照群(モデル群)と比べ、その体重の増加が緩くなり、かつ血中脂質が低下し、そして糖尿病に関連する様々な指標、たとえば空腹時血糖レベルも低下し、また耐糖能も顕著に改善した。そのため、前記菌株は糖尿病およびその関連疾患(たとえば心血管疾患、肥満疾患)の予防と治療に使用することができる。
The present invention provides the use of Phycaribacterium longum in the treatment and prevention of diabetes and related diseases (eg, cardiovascular disease, obesity disease). In subjects consuming high-fat foods, the strain Faecalibacterium longum CM04-06 (i) suppressed weight gain in the subject, (ii) decreased blood lipids, (iii) decreased fasting blood glucose levels, (iv). It has one or more uses selected from the group consisting of improved glucose tolerance. According to one preferred example of the present invention, a
組成物及びその使用
また、本発明は組成物、好ましくは薬物組成物を提供する。前記組成物は有効量のフィーカリバクテリウム・ロンガムを含み、一つの好適な例において、前記組成物はさらに牛乳成長因子を含む。一つの好適な例において、前記組成物はさらに乳酸菌、ビフィドバクテリウム、ラクトバチルス・アシドフィルス、またはこれらの組み合せからなる群から選ばれるプロバイオティクス、ならびに/あるいははフラクトオリゴ糖(FOS)、ガラクトオリゴ糖(GOS)、キシロオリゴ糖(XOS)、乳果オリゴ糖(LACT)、大豆オリゴ糖(SOS)、イヌリン(Inulin)、またはこれらの組み合せからなる群から選ばれるプレバイオティクスを含む。
Compositions and Their Use The present invention also provides compositions, preferably drug compositions. The composition comprises an effective amount of Phycaribacterium longum, and in one preferred example, the composition further comprises a milk growth factor. In one preferred example, the composition further comprises a probiotic selected from the group consisting of lactic acid bacteria, bifidobacteria, lactobacillus acidophilus, or a combination thereof, and / or fructooligosaccharide (FOS), galactooligosaccharide. Includes prebiotics selected from the group consisting of (GOS), xylooligosaccharides (XOS), milk fruit oligosaccharides (LACT), soybean oligosaccharides (SOS), inulin, or combinations thereof.
一つの好適な例において、前記の組成物は液体製剤、固体製剤、半固体製剤である。 In one preferred example, the composition is a liquid formulation, a solid formulation, a semi-solid formulation.
一つの好適な例において、前記の液体製剤は、溶液製品または懸濁液製品からなる群から選ばれる。 In one preferred example, the liquid formulation is selected from the group consisting of solution products or suspension products.
一つの好適な例において、前記の組成物の剤形は、粉末剤、散剤、錠剤、糖衣剤錠剤、カプセル剤、顆粒剤、懸濁剤、溶液剤、シロップ剤、ドロップ剤、およびトローチ剤からなる群から選ばれる。 In one preferred example, the dosage form of the composition is from powders, powders, tablets, sugar-coated tablets, capsules, granules, suspensions, solutions, syrups, drops, and lozenges. Selected from the group of
本発明の薬物組成物は薬物の錠剤、注射剤またはカプセルのいずれかの形態で投与することができ、前記薬物製剤は賦形剤、薬物的に許容される媒体および担体を含み、これらの物質は投与形態によって選択することができる。本発明における薬物製剤はさらに補助する活性成分を含んでもよい。 The drug compositions of the invention can be administered in the form of tablets, injections or capsules of drugs, said drug formulations comprising excipients, pharmaceutically acceptable vehicles and carriers, these substances. Can be selected according to the dosage form. The drug formulation in the present invention may further contain an auxiliary active ingredient.
乳糖、ブドウ糖、ショ糖、ソルビトール、マンニトール、デンプン、アラビアゴム、リン酸カルシウム、アルギン酸塩、ゼラチン、ケイ酸カルシウム、微細結晶セルロース、ポリビニルピロリドン(PVP)、セルロース、水、シロップ、メチルセルロース、ヒドロキシ安息香酸メチル、ヒドロキシ安息香酸プロピル、タルク、ステアリン酸マグネシウムや鉱物油などはいずれも本発明における薬物組成物の担体、賦形剤や希釈剤などとして使用することができる。 Lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, excipients, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone (PVP), cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, All of propyl hydroxybenzoate, talc, magnesium stearate, mineral oil and the like can be used as carriers, excipients, diluents and the like of the drug composition in the present invention.
また、本発明の薬物組成物は、さらに、潤滑剤、湿潤剤、乳化剤、懸濁液安定剤、防腐剤、甘味剤や香料などを含んでもよい。本発明の薬物組成物は、薬物組成物の活性成分、すなわち、微生物が胃酸に破壊されずに順調に胃を通過することができるように、様々な公知の方法によって腸溶性コーティング製剤として生産してもよい。 In addition, the drug composition of the present invention may further contain a lubricant, a wetting agent, an emulsifier, a suspension stabilizer, a preservative, a sweetener, a fragrance and the like. The drug composition of the present invention is produced as an enteric coating preparation by various known methods so that the active ingredient of the drug composition, that is, microorganisms can smoothly pass through the stomach without being destroyed by gastric acid. You may.
さらに、本発明の微生物は通常の方法によって製造されたカプセルの形態で使用してもよい。たとえば、標準賦形剤と本発明の凍結乾燥された微生物を混合して小球のピルとした後、ピルをゼラチンのカプセルに充填する。また、本発明の微生物と薬物的に許容される賦形剤、たとえば液体ガム、セルロース、ケイ酸塩や鉱物油などを混合して懸濁液または分散液とし、この懸濁液または分散液を軟ゼラチンカプセルに充填してもよい。 In addition, the microorganisms of the invention may be used in the form of capsules produced by conventional methods. For example, standard excipients and lyophilized microorganisms of the invention are mixed to form globules of pills, which are then filled into gelatin capsules. Further, the microorganism of the present invention and a pharmaceutically acceptable excipient such as liquid gum, cellulose, silicate or mineral oil are mixed to form a suspension or dispersion, and this suspension or dispersion is used. It may be filled in a soft gelatin capsule.
本発明の薬物組成物は腸溶性コーティング錠として経口投与で使用してもよい。本出願における用語「腸溶性コーティング」は、すべての通常の薬物的に許容される腸溶性コーティングを含み、これらのコーティングは胃酸に分解されないが、小腸において十分に分解して迅速に本発明の微生物を放出することができる。本発明の腸溶性コーティングは合成胃酸、たとえばpH=1のHCl溶液において36〜38℃で2時間以上維持し、かつ好ましくは合成腸液、たとえばpH=7.0の緩衝液において1.0時間内で分解する。 The drug composition of the present invention may be used orally as an enteric coated tablet. The term "enteric coating" in the present application includes all conventional pharmaceutically acceptable enteric coatings, which are not degraded to gastric acid, but are fully degraded in the small intestine and rapidly decomposed by the microorganisms of the invention. Can be released. The enteric coating of the present invention is maintained at 36-38 ° C. for 2 hours or longer in synthetic gastric acid, eg, a pH = 1 HCl solution, and preferably decomposes in synthetic enteric fluid, eg, a pH = 7.0 buffer, within 1.0 hour.
本発明の腸溶性コーティングは1錠あたりに約16〜30 mg、好ましくは16〜25 mg、より好ましくは16〜20 mgでコーティングされる。本発明における腸溶性コーティングの厚さは5〜100μm、理想の厚さは20〜80μmである。腸溶性コーティングの成分はすでに公開されて既知の通常の重合体が選ばれる。 The enteric coating of the present invention is coated with about 16-30 mg, preferably 16-25 mg, more preferably 16-20 mg per tablet. The thickness of the enteric coating in the present invention is 5 to 100 μm, and the ideal thickness is 20 to 80 μm. The components of the enteric coating are selected from conventional polymers that have already been published and are known.
本発明の好適な腸溶性コーティングは酢酸セルロースのフタル酸エステル重合体またはトリメリット酸エステル重合体とメタクリル酸の共重合体(たとえば、40%以上のメタクリル酸とフタル酸ヒドロキシプロピルメチルセルロースまたはそのエステル系誘導体を含むメタクリル酸の共重合体)で製造される。 Suitable enteric coatings of the present invention are phthalate ester polymers of cellulose acetate or trimellitic acid ester polymers and copolymers of methacrylic acid (eg, 40% or more methacrylic acid and hydroxypropylmethyl phthalate or esters thereof). It is made of a methacrylic acid copolymer containing a derivative).
本発明における腸溶性コーティングに使用される酢酸フタル酸セルロースの粘度は約45〜90 cpで、アセチル含有量は17〜26%で、フタル酸含有量は30〜40%である。腸溶性コーティングに使用されるトリメリット酸酢酸セルロースの粘度は約5〜21 csで、アセチル含有量は17〜26%である。トリメリット酸酢酸セルロースはイーストマン・コダック社によって生産され、本発明における腸溶性コーティング材料に使用することができる。 The cellulose acetate phthalate used in the enteric coating in the present invention has a viscosity of about 45-90 cp, an acetyl content of 17-26% and a phthalic acid content of 30-40%. Cellulose trimellitic acid acetate used in enteric coatings has a viscosity of about 5-21 cs and an acetyl content of 17-26%. Cellulose acetate trimellitic acid is produced by Eastman Kodak and can be used in the enteric coating material of the present invention.
本発明の腸溶性コーティングに使用されるフタル酸ヒドロキシプロピルメチルセルロースは、分子量が一般的に20,000〜130,000ダルトンで、理想の分子量が80,000〜100,000ダルトンで、ヒドロキシプロピル含有量は5〜10%で、メトキシ含有量は18〜24%で、フタロイル含有量は21〜35%である。 The hydroxypropylmethylcellulose phthalate used in the enteric coating of the present invention generally has a molecular weight of 20,000 to 130,000 daltons, an ideal molecular weight of 80,000 to 100,000 daltons, a hydroxypropyl content of 5 to 10%, and methoxy. The content is 18-24% and the phthaloyl content is 21-35%.
本発明の腸溶性コーティングに使用されるフタル酸ヒドロキシプロピルメチルセルロースはHP50で、日本信越化学工業株式会社によって生産される。HP50は6〜10%のヒドロキシプロピル基、20〜24%のメトキシ基、21〜27%のプロピル基を含有し、その分子量は84,000ダルトンである。もう1種類の腸溶性コーティング物質はHP55で、HP55は5〜9%のフタル酸ヒドロキシプロピルメチルセルロース、18〜22%のメトキシ基、27〜35%のフタル酸を含有し、その分子量は78,000ダルトンである。 The hydroxypropylmethylcellulose phthalate used in the enteric coating of the present invention is HP50 and is produced by Shin-Etsu Chemical Co., Ltd. of Japan. HP50 contains 6-10% hydroxypropyl group, 20-24% methoxy group, 21-27% propyl group and has a molecular weight of 84,000 daltons. Another enteric coating is HP55, which contains 5-9% hydroxypropylmethylcellulose phthalate, 18-22% methoxy groups, 27-35% phthalic acid and has a molecular weight of 78,000 daltons. is there.
本発明の腸溶性コーティングは、通常の方法で腸溶性コーティング溶液をコアに噴霧することによって製造される。当該腸溶性コーティング方法に使用される溶媒はアルコール類(たとえばエタノール)、ケトン類(たとえばアセトン)、ハロ炭化水素化合物(たとえばジクロロメタン)、またはこれらの組み合わせである。軟化剤、たとえばフタル酸ジ-n-ブチルやトリ酢酸グリセリンを腸溶性コーティング溶液に入れ、その比率は1部のコーティング物に対して約0.05部または約0.3部の軟化剤である。噴霧方法は連続に行われることが好ましく、噴霧される材料の量はコーティングに使用される条件によって制御することができる。噴霧の圧力は任意に調整することができるが、一般的に、平均1〜1.5バールの圧力で理想の結果が得られる。 The enteric coating of the present invention is produced by spraying an enteric coating solution onto a core in a conventional manner. The solvent used in the enteric coating method is alcohols (eg ethanol), ketones (eg acetone), halohydrocarbon compounds (eg dichloromethane), or combinations thereof. A softener, such as di-n-butyl phthalate or glycerin triacetate, is placed in an enteric coating solution and the ratio is about 0.05 or about 0.3 parts of the softener to one part of the coating. The spraying method is preferably continuous and the amount of material sprayed can be controlled by the conditions used for the coating. The spray pressure can be adjusted as desired, but in general, ideal results are obtained with an average pressure of 1-1.5 bar.
明細書における「薬物有効量」とは、ヒトおよび/または動物に機能や活性があり、且つヒトおよび/または動物にとって受けられる量である。たとえば、本発明において、1×10〜1×1010cfu/mlまたはcfu/g(特に、1×104〜1×1010cfu/mlまたはcfu/g、より特に、1×106〜1×1010cfu/mlまたはcfu/g)のフィーカリバクテリウム・ロンガムおよび/またはその代謝産物を含有する製剤を製造することができる。 As used herein, a "drug effective amount" is an amount that has a function or activity in humans and / or animals and is acceptable to humans and / or animals. For example, in the present invention, 1 × 10 to 1 × 10 10 cfu / ml or cfu / g (particularly 1 × 10 4 to 1 × 10 10 cfu / ml or cfu / g, more particularly 1 × 10 6 to 1). × 10 10 cfu / ml or cfu / g) of Phycaribacterium longum and / or its metabolites can be produced.
薬物組成物の製造に使用される場合、用いられるフィーカリバクテリウム・ロンガムまたはその代謝産物の有効使用量は、施用の様態と治療しようとする疾患の重篤度によって変更することができる。内服に適する投与量の様態は、固体または液体の薬学的に許容される担体と密接に混合した約1×10〜1×1010cfu/mlまたはcfu/g(特に、1×104〜1×1010cfu/mlまたはcfu/g、より特に、1×106〜1×1010cfu/mlまたはcfu/g)の活性フィーカリバクテリウム・ロンガムまたは発酵による活性成分を含む。この投与量の方案を調節することにより、最適な治療応答を提供することができる。たとえば、治療状況の切望によって、毎日数回に分けた投与量、または比率的に減少する投与量で投与することができる。 When used in the manufacture of drug compositions, the effective use of Phycaribacterium longum or its metabolites used can vary depending on the mode of application and the severity of the disease to be treated. Suitable dosage modes for oral administration are approximately 1 x 10 to 1 x 10 10 cfu / ml or cfu / g (particularly 1 x 10 4 to 1) in close mixing with solid or liquid pharmaceutically acceptable carriers. Includes x 10 10 cfu / ml or cfu / g, and more particularly 1 x 10 6 to 1 x 10 10 cfu / ml or cfu / g) active phicalobacter longum or fermented active ingredients. By adjusting this dosage regimen, an optimal therapeutic response can be provided. For example, depending on the coveted treatment situation, it can be administered in several divided doses daily or in a proportionately decreasing dose.
前記のフィーカリバクテリウム・ロンガムまたはその代謝産物は経口投与などの形態によって投与してもよい。固体担体は、澱粉、ラクトース、リン酸水素カルシウム、微晶質セルロース、ショ糖とカオリンを、液体担体は、培地、ポリエチレングリコール、ノニオン性界面活性剤と食用油(例えばトウモロコシ油、落花生油と胡麻油)を含むが、フィーカリバクテリウム・ロンガムまたはその代謝産物の特性と所期の特定の投与形態に適するものであればよい。薬物組成物の製造に通常用いられる佐剤も有利的に含まれるが、例えば、矯味剤、色素、防腐剤及びビタミンE、ビタミンC、BHTとBHAのような酸化防止剤などが挙げられる。 The Phycaribacterium longum or a metabolite thereof may be administered in a form such as oral administration. Solid carriers include starch, lactose, calcium hydrogen phosphate, microcrystalline cellulose, sucrose and kaolin, and liquid carriers include medium, polyethylene glycol, nonionic surfactants and edible oils (eg corn oil, peanut oil and sesame oil). ), But it may be suitable for the characteristics of Phycaribacterium longum or its metabolite and the desired specific dosage form. Also advantageously included are adjuvants commonly used in the manufacture of drug compositions, such as syrups, pigments, preservatives and antioxidants such as Vitamin E, Vitamin C, BHT and BHA.
製造の容易さ及び投与の面から、好ましい薬物組成物は、固形組成物、特に錠剤及び固体充填或いは液体充填のカプセルである。経口投与が好ましい。 From the standpoint of ease of manufacture and administration, preferred drug compositions are solid compositions, especially tablets and solid-filled or liquid-filled capsules. Oral administration is preferred.
本発明の組成物を前記個体に施用し、毎日1回または複数回投与する。投与量の単位はその形態で分けられる、ヒトまたはほかのすべての哺乳動物の個体に適する投与量を示す。各単位は薬物的に許容される担体と有効治療量の本発明の微生物を含む。投与量は患者の体重および糖尿病の重篤度、含まれる補充活性成分および使用される微生物によって変わる。また、可能であれば、分けて投与してもよく、かつ必要によって連続に投与してもよい。そのため、前記投与量は本発明の限定にならない。また、本発明における「組成物」は薬品だけでなく、機能性食品および健康食品にしてもよい。一つの好適な例において、前記組成物は、飲料、食品、薬品、動物飼料などを含む。 The composition of the present invention is applied to the individual and administered once or multiple times daily. The unit of dose indicates the dose suitable for a human or all other mammalian individuals, which is divided by its form. Each unit comprises a pharmaceutically acceptable carrier and an effective therapeutic amount of the microorganism of the invention. The dosage depends on the patient's weight and severity of diabetes, the supplementary active ingredients contained and the microorganisms used. Further, if possible, they may be administered separately, and if necessary, they may be administered continuously. Therefore, the dose is not limited to the present invention. Moreover, the "composition" in the present invention may be not only a drug but also a functional food and a health food. In one preferred example, the composition comprises beverages, foods, medicines, animal feeds and the like.
本発明の一つの好適な例において、さらに、有効量のフィーカリバクテリウム・ロンガムおよび/またはその代謝産物と、残量の食品的に許容される担体とを含む食品組成物を提供し、前記の食品組成物の剤形は固体、乳製品、溶液製品、粉末製品、または懸濁液製品を含む。もう一つの好適な例において、前記食品組成物はさらに牛乳成長因子を含んでもよい。 In one preferred example of the present invention, a food composition comprising an effective amount of Phycaribacterium longum and / or a metabolite thereof and a remaining amount of a food-acceptable carrier is provided. Dosage forms of food compositions include solid, dairy, solution products, powder products, or suspension products. In another preferred example, the food composition may further comprise milk growth factor.
一つの好適な例において、前記組成物の配合は、1×10〜1×1010cfu/mLのフィーカリバクテリウム・ロンガムおよび/またはその代謝産物と、食品的にまたは薬学的に許容される担体、および/または賦形剤とである。 In one preferred example, the formulation of the composition is foodally or pharmaceutically acceptable with 1 x 10 to 1 x 10 10 cfu / mL Phycaribacterium longum and / or its metabolites. Carriers and / or excipients.
もう一つの好適な例において、前記組成物の配合は、1×106〜1×1010cfu/mLのフィーカリバクテリウム・ロンガムおよび/またはその代謝産物と、食品的にまたは薬学的に許容される担体、および/または賦形剤とである。 In another preferred example, the formulation of the composition is foodally or pharmaceutically acceptable with 1 × 10 6 to 1 × 10 10 cfu / mL Phycaribacterium longum and / or its metabolites. Carriers and / or excipients to be used.
マイクロ生態製剤
マイクロ生態製剤はプロバイオティクスおよび代謝産物を含む生物製剤またはプロバイオティクスを増加させる食事サプリメントで、腸内マイクロ生態のバランスを調節、維持することによって、人体の健康レベルを向上させる目的を実現することができる。主にプロバイオティクス、プレバイオティクスおよびバイオスタイム(合生元、Biostime)を含む。
Microecologics Microecologics are biologics or dietary supplements that increase probiotics, including probiotics and metabolites, with the goal of improving the health level of the human body by adjusting and maintaining the balance of intestinal microecology. Can be realized. Mainly includes probiotics, prebiotics and biostime (biostime).
本発明において、前記マイクロ生態製剤は(a)安全有効量のフィーカリバクテリウム・ロンガムおよび/またはその代謝産物と、(b)食品的に許容される担体または薬学的に許容される担体とを含む。一つの好適な例において、前記製剤はさらに成長因子を含む(たとえば牛乳成長因子、好ましくは、ビタミン類物質、プリン類物質、および/またはピリミジンを含む)。 In the present invention, the microecologic preparation comprises (a) a safe and effective amount of Phycaribacterium longum and / or a metabolite thereof, and (b) a food-acceptable carrier or a pharmaceutically acceptable carrier. Including. In one preferred example, the formulation further comprises growth factors (eg, milk growth factors, preferably vitamins, purines, and / or pyrimidines).
フィーカリバクテリウム・ロンガムの生産方法
通常、フィーカリバクテリウム・ロンガムは通常の方法で製造することができる。
Method for Producing Phycaribacterium Longum Generally, Phycaribacterium longum can be produced by a usual method.
本発明において、大規模にフィーカリバクテリウム・ロンガムを生産する方法、具体的に、
(a)適切な培養条件において、前記のフィーカリバクテリウム・ロンガムを培養することによって、培養産物を得る工程、
(b)任意に、前記培養産物からフィーカリバクテリウム・ロンガムの菌体および/またはその代謝産物を分離する工程、ならびに
(c)任意に、工程(b)で分離されたフィーカリバクテリウム・ロンガムの菌体および/またはその代謝産物を食品的に許容される担体または薬学的に許容される担体と混合することによって、組成物を製造する工程
を含む方法を提供する。
In the present invention, a method for producing Phycaribacterium longum on a large scale, specifically,
(A) A step of obtaining a culture product by culturing the above-mentioned Phicalibacterium longum under appropriate culture conditions.
(B) Optionally, a step of separating the bacterial cells of Phicalibacterium longum and / or its metabolite from the culture product, and (c) optionally, the step (b) of the Ficalobacterium isolated in step (b). Provided is a method comprising the step of producing a composition by mixing a longum cell and / or a metabolite thereof with a food-acceptable carrier or a pharmaceutically acceptable carrier.
体重、空腹時血糖および/または血中脂質を低下させる方法
もう一つの好適な例において、前記方法は、本発明の薬物組成物、食品組成物、飲料組成物、またはこれらの組み合わせを摂取することを含む。前記実験対象はヒトである。
Methods of Lowering Body Weight, Fasting Blood Glucose and / or Blood Lipids In another preferred example, the method is to ingest the drug composition, food composition, beverage composition, or a combination thereof of the present invention. including. The subject of the experiment is a human.
もう一つの好適な例において、前記方法は、本発明の薬物組成物、食品組成物、または動物飼料、またはこれらの組み合わせを摂取することを含む。前記実験対象は動物、好ましくはネズミ類、ウサギ類である。 In another preferred example, the method comprises ingesting the drug composition, food composition, or animal feed of the present invention, or a combination thereof. The subjects of the experiment are animals, preferably mice and rabbits.
耐糖能を向上させる方法
もう一つの好適な例において、前記方法は、本発明の薬物組成物、食品組成物、飲料組成物、またはこれらの組み合わせを摂取することを含む。前記実験対象はヒトである。
Methods for Improving Glucose Tolerance In another preferred example, the method comprises ingesting the drug composition, food composition, beverage composition, or a combination thereof of the present invention. The subject of the experiment is a human.
もう一つの好適な例において、前記方法は、本発明の薬物組成物、食品組成物、または動物飼料、またはこれらの組み合わせを摂取することを含む。前記実験対象は動物、好ましくはネズミ類、ウサギ類である。 In another preferred example, the method comprises ingesting the drug composition, food composition, or animal feed of the present invention, or a combination thereof. The subjects of the experiment are animals, preferably mice and rabbits.
菌株の寄託
本発明の菌種であるフィーカリバクテリウム・ロンガムFaecalibacterium longum CM04-06(寄託名称と同様)は、既に2016年6月13日に中国微生物菌種保蔵管理委員会普通微生物センター(CGMCC)に寄託され、住所は中国北京市朝陽区北辰西路1号院3号で、寄託番号はそれぞれCGMCC 1.5208である。
Strain Deposit Faecalibacterium longum CM04-06 (same as the deposit name), which is the strain of the present invention, has already been released on June 13, 2016 at the Ordinary Microbial Center (CGMCC) of the China Microbial Species Preservation Management Committee. ), The address is No. 3 of Hokushin West Road, Chaoyang District, Beijing, China, and the deposit number is CGMCC 1.5208.
本発明の主な利点は以下の通りである。
(a)本発明のフィーカリバクテリウム・ロンガムは顕著に体重、血中脂質、空腹時血糖レベルを低下させることができる。
(b)本発明のフィーカリバクテリウム・ロンガムは顕著に肥満およびその関連疾患(たとえば心血管疾患)に関連する指標(たとえばコレステロールやトリグリセリド)を低下させることができる。
(c)本発明のフィーカリバクテリウム・ロンガムは顕著に総コレステロール、トリグリセリド、低密度リポタンパク質のレベルを低下させることができる。
(d)本発明のフィーカリバクテリウム・ロンガムは顕著に高密度リポタンパク質のレベルを向上させることができる。
(e)本発明のフィーカリバクテリウム・ロンガムは顕著に耐糖能を改善することができる。
The main advantages of the present invention are as follows.
(A) The Phycaribacterium longum of the present invention can significantly reduce body weight, blood lipids, and fasting blood glucose levels.
(B) The Phycaribacterium longum of the present invention can significantly reduce indicators (eg, cholesterol and triglycerides) associated with obesity and related diseases (eg, cardiovascular disease).
(C) The Phycaribacterium longum of the present invention can significantly reduce the levels of total cholesterol, triglyceride and low density lipoprotein.
(D) The Phycaribacterium longum of the present invention can significantly improve the level of high density lipoprotein.
(E) The Phycaribacterium longum of the present invention can significantly improve glucose tolerance.
以下、具体的な実施例によって、さらに本発明を説明する。これらの実施例は本発明を説明するために用いられるものだけで、本発明の範囲の制限にはならないと理解されるものである。以下の実施例で具体的な条件が示されていない実験方法は、通常、たとえばSambrookら、「モレキュラー・クローニング:研究室マニュアル」(ニューヨーク、コールド・スプリング・ハーバー研究所出版社、1989)に記載の条件、あるいは「微生物学:実験マニュアル」(James CappuccinoとNatalie Sherman編、Pearson Education出版社)に記載の条件、あるいはメーカーのお薦めの条件に従う。 Hereinafter, the present invention will be further described with reference to specific examples. It is understood that these examples are used only to illustrate the invention and do not limit the scope of the invention. Experimental methods for which specific conditions are not shown in the following examples are usually described, for example, in Sambrook et al., "Molecular Cloning: Laboratory Manual" (Cold Spring Harbor Laboratory, NY, 1989). Or the conditions described in "Microbiology: Experimental Manual" (edited by James Cappuccino and Natalie Sherman, Pearson Education Publisher), or the conditions recommended by the manufacturer.
特に説明しない限り、実施例で使用された材料はいずれも市販品である。 Unless otherwise specified, all the materials used in the examples are commercially available products.
Faecalibacterium prausnitzii ATCC 27768は、以下ATCC 27768と略し、米国タイプカルチャーコレクション(American Type Culture Collection)から購入され、寄託番号はATCC 27768である。 Faecalibacterium prausnitzii ATCC 27768 is abbreviated as ATCC 27768, purchased from the American Type Culture Collection, and the deposit number is ATCC 27768.
実施例1 フィーカリバクテリウム・ロンガムCM04-06の選別と同定
1.1 CM04-06の分離と培養
本発明に記載のフィーカリバクテリウム・ロンガムCM04-06(以下、CM04-06と略する)は深セン市の1名の健康の児童(男性)の糞便サンプルから分離されたものである。分離と培養の環境は厳密な嫌気条件で、具体的な分離過程は、嫌気グローブボックスにおいて0.2g程度の糞便サンプルを取り、1mLの無菌PBSで懸濁分散を行い、十分に振とうして均一に混合した後、勾配希釈を行って塗布し、培地は嫌気のPYG培地(HuanKai Microbial社)を使用し、具体的な成分は下記表に示す。
Example 1 Selection and identification of Phycaribacterium longum CM04-06
1.1 Separation and culture of CM04-06 The Phycaribacterium longum CM04-06 (hereinafter abbreviated as CM04-06) described in the present invention is isolated from the fecal sample of one healthy child (male) in Shenzhen City. It was done. The separation and culture environment is strict anaerobic conditions, and the specific separation process is as follows: Take a stool sample of about 0.2 g in an anaerobic glove box, suspend and disperse with 1 mL of sterile PBS, and shake well to make it uniform. After mixing with, apply with gradient dilution, and use anaerobic PYG medium (HuanKai Microbial) as the medium, and the specific components are shown in the table below.
無機塩溶液の配合は以下の通りである。 The composition of the inorganic salt solution is as follows.
プレートを塗布して37℃の嫌気条件において3〜4日培養し、プレートの表面に集落ができたら、単一集落を取って画線分離を行い、純粋な培養菌株を得るまで繰り返し、分離された菌株をグリセリンで-80℃で冷凍保存した。 The plate is applied and cultured under anaerobic conditions at 37 ° C for 3 to 4 days. When colonies are formed on the surface of the plate, a single colony is taken and streaked, and the cells are separated by repeating until a pure cultured strain is obtained. The strain was frozen and stored in glycerin at -80 ° C.
1.2 フィーカリバクテリウム・ロンガムCM04-06の16S rDNAの同定
(1)ゲノムの抽出:分離された菌株を培養し、菌濃度が108cfu/mlのスケールに達したら2mlの菌液を取ってゲノムDNAの抽出を行った。
1.2 Identification of 16S rDNA of Phycalibacterium longum CM04-06 (1) Genome extraction: Cultivate the isolated strains, and when the bacterial concentration reaches the scale of 10 8 cfu / ml, take 2 ml of bacterial solution. Genomic DNA was extracted.
(2)16S rDNAのPCR増幅:DNAを鋳型として16S rDNAの増幅を行い、増幅プライマーとして16S rDNAの通常の増幅プライマー:8F-1492R(5’-AGAGTTTGATCATGGCTCAG-3’(配列番号2)および5’-TAGGGTTACCTTGTTACGACTT-3’(配列番号3))を使用し、PCR増幅プログラムは以下の通りである。 (2) PCR amplification of 16S rDNA: Amplification of 16S rDNA using DNA as a template, and normal amplification primer of 16S rDNA as an amplification primer: 8F-1492R (5'-AGAGTTTGATCATGGCTCAG-3'(SEQ ID NO: 2) and 5' -Using TAGGGTTACCTTGTTACGACTT-3'(SEQ ID NO: 3), the PCR amplification program is as follows.
(3)精製、配列決定:得られたPCR産物に対して磁気ビーズ精製を行った後、電気泳動による検出を行い、16S rDNAのバンドは約1.5k程度に位置し、精製された産物に対して3730配列決定を行った。 (3) Purification and sequencing: After purifying the obtained PCR product with magnetic beads, detection was performed by electrophoresis. The 16S rDNA band was located at about 1.5 k, and the purified product was subjected to. 3730 was sequenced.
(4)16S rDNA配列のデータベースのアラインメント:配列決定によって1372bpの16S rDNA配列を得、この配列をEzTaxon-eデータベースでアラインメントし、初歩的に菌株の種の分類情報を得た。16S rDNAの情報から初歩的にCM04-06がFaecalibacterium属に属する新しい種であると判定できた。 (4) Database alignment of 16S rDNA sequence: A 1372 bp 16S rDNA sequence was obtained by sequencing, and this sequence was aligned with the EzTaxon-e database to obtain rudimentary strain classification information. From the information of 16S rDNA, it was possible to determine that CM04-06 is a new species belonging to the genus Faecalibacterium.
CM04-06の16S rDNA配列は配列番号1で、以下の通りである。 The 16S rDNA sequence of CM04-06 is SEQ ID NO: 1 and is as follows.
1.3 CM04-06の16S rDNAの進化分析
CM04-06の進化分析は16S rDNA配列を使用し、CM04-06の16S rDNA配列でEzTaxon-eデータベースのアラインメントを行い、CM04-06と近縁の種を得、これらの種をCM04-06の16S rDNA配列と配列のアラインメントを行った後、Mega5ソフトで近隣結合法(neighbour-joining)系統樹を作成した。
1.3 Evolutionary analysis of 16S rDNA in CM04-06
The evolutionary analysis of CM04-06 used 16S rDNA sequences and aligned the EzTaxon-e database with the 16S rDNA sequences of CM04-06 to obtain species closely related to CM04-06, which were used in CM04-06. After aligning the 16S rDNA sequence with the sequence, a neighbor-joining phylogenetic tree was created with Mega5 software.
1.4 CM04-06の微生物学的特徴
(1)形態学的特徴:CM04-06は嫌気環境において37℃で2〜3日培養した後、集落が黄白色で、含水量が高く、すこし粘稠で、ほぼ円形で、不透明で、平たくて中央が突起し、集落の直径が約2〜3mmであった(図1)。
1.4 Microbiological characteristics of CM04-06 (1) Morphological characteristics: CM04-06 is yellowish white, has a high water content, and is slightly viscous after culturing at 37 ° C for 2 to 3 days in an anaerobic environment. , Almost circular, opaque, flat, with a protruding center, and the diameter of the settlement was about 2-3 mm (Fig. 1).
(2)顕微学的特徴:顕微鏡において1000倍に拡大し、CM04-06の菌体は長桿状で、グラム染色の反応は陰性で、芽胞と鞭毛が見られず、菌体の直径が約1μmで、長さが4〜10μmであった(図2)。 (2) Microscopic features: Magnified 1000 times under a microscope, CM04-06 cells were long rod-shaped, Gram stain reaction was negative, spores and flagella were not seen, and the diameter of the cells was about 1 μm. The length was 4 to 10 μm (Fig. 2).
(3)生理学・生物化学的特徴:オキシダーゼおよびカタラーゼ反応がいずれも陰性で、生長温度の範囲が30〜45℃で、pH値の範囲が4.0〜9.0で、最適の温度およびpH値が37℃およびpH 7.0であった。3%のNaClに耐えることができた。CM04-06と一番近縁の参照菌ATCC 27768の生理学・生物化学反応(基質の利用状況API 20Aおよび酵素反応API ZYMを含む)の比較は下記表に示す(+は陽性反応を、-は陰性反応を、wは弱陽性反応を表す)。 (3) Physiological and biochemical characteristics: Both oxidase and catalase reactions are negative, the growth temperature range is 30 to 45 ° C, the pH value range is 4.0 to 9.0, and the optimum temperature and pH value is 37 ° C. And pH 7.0. It was able to withstand 3% NaCl. A comparison of the physiological and biochemical reactions (including substrate utilization API 20A and enzyme reaction API ZYM) of CM04-06 and the closest reference bacterium ATCC 27768 is shown in the table below (+ indicates a positive reaction,-is a positive reaction. Negative reaction, w stands for weak positive reaction).
以上のCM04-06と参照菌の生理学・生物化学反応の比較によって、CM04-06はラフィノースとトレハロースの利用、エスクリンとゼラチンの加水分解およびエステラーゼ(C4)、バリンアリルアミダーゼ、シスチンアリルアミダーゼ、キモトリプシン、ナフトール-AS-BI-リン酸加水分解酵素、β-グルクロニダーゼ、α-グルコシダーゼおよびN-アセチル-グルコサミニダーゼの活性で顕著に異なったことが示され、CM04-06が既知の菌と異なる新種であることが証明された。 By comparing the physiological and biochemical reactions of CM04-06 and the reference bacterium, CM04-06 uses raffinose and trehalose, hydrolyzes esculin and gelatin and esterase (C4), valine allyl amidase, cystine allyl amidase, chymotrypsin, It was shown that the activities of naphthol-AS-BI-phosphate hydrolase, β-glucuronidase, α-glucosidase and N-acetyl-glucosaminidase were significantly different, and CM04-06 was a new species different from the known bacteria. Was proved.
1.5 細胞脂肪酸の分析
定常期まで培養したCM04-06をFaecalibacterium prausnitzii ATCC 27768(以下、ATCC 27768と略し、米国タイプカルチャーコレクション(American Type Culture Collection)から購入され、寄託番号はATCC 27768である)の菌体を収集した後、細胞脂肪酸を抽出し、検出した。ガスクロマトグラフィーによって2株の菌の細胞脂肪酸の成分の含有量および違いを分析した。
1.5 Analysis of cellular fatty acids CM04-06 cultured to the stationary phase is a bacterium of Faecalibacterium prausnitzii ATCC 27768 (hereinafter abbreviated as ATCC 27768, purchased from the American Type Culture Collection, and the deposit number is ATCC 27768). After collecting the body, cellular fatty acids were extracted and detected. The content and difference of the cellular fatty acid components of the two strains were analyzed by gas chromatography.
このように、CM04-06表現型、16S rDNA配列および生理学・生物化学反応で、CM04-06が新種であることが示され、それをフィーカリバクテリウム・ロンガムFaecalibacterium longumと名付けた。 Thus, the CM04-06 phenotype, 16S rDNA sequence and physiological / biochemical reactions showed that CM04-06 was a new species, named Faecalibacterium longum.
実施例2 フィーカリバクテリウム・ロンガムFaecalibacterium longum CM04-06の生物活性物質
2.1 短鎖脂肪酸(SCFA)の検出
(1)サンプルの調製:48h培養したCM04-06菌液1mlを取り、12000r /minで5min遠心し、上清液を吸い取り、使用に備えた。
Example 2 Bioactive substance of Faecalibacterium longum CM04-06
2.1 Detection of short-chain fatty acids (SCFA) (1) Sample preparation: 1 ml of CM04-06 bacterial solution cultured for 48 hours was taken, centrifuged at 12000 r / min for 5 min, and the supernatant was absorbed to prepare for use.
(2)SCFAの測定:短鎖脂肪酸の測定は外標準法を使用し、酢酸、プロピオン酸、酪酸、吉草酸で標準曲線の作成を行った。アジレントのガスクロマトグラフ(GC-7890B, Agilent)を使用し、HP-INNOWax(Cross-Linked PEG)、30m×0.25mm×0.25umの毛細柱によって分析し、検出器は水素炎イオン化検出器で、GCパラメーターの設定はカラム温度:180〜200℃、気化室温度:240℃、検出温度:210℃、仕込み量:2μL、キャリアガス流量:N2,50mL/ min、水素ガス流量:50 mL/ min、空気流量:600〜700 mL/ minであった。 (2) Measurement of SCFA: A standard curve was prepared for acetic acid, propionic acid, butyric acid, and valeric acid using the external standard method for the measurement of short-chain fatty acids. Analyzing with HP-INNOWax (Cross-Linked PEG), 30m x 0.25mm x 0.25um capillary using an Agilent gas chromatograph (GC-7890B, Agilent), the detector is a hydrogen flame ionization detector, GC Parameter settings are column temperature: 180-200 ° C, vaporization chamber temperature: 240 ° C, detection temperature: 210 ° C, charge amount: 2 μL, carrier gas flow rate: N 2 , 50 mL / min, hydrogen gas flow rate: 50 mL / min, Air flow rate: 600-700 mL / min.
(3)結果:測定したところ、SCFAの収量は、ギ酸(7.62mmol/L)、酢酸(44.8 mmol/L)、酪酸(40.03 mmol/L)であった。 (3) Results: As measured, the yield of SCFA was formic acid (7.62 mmol / L), acetic acid (44.8 mmol / L), and butyric acid (40.03 mmol / L).
2.2 有機酸の検出
(1)サンプルの調製:2.1部分と同様である。
2.2 Detection of organic acids (1) Sample preparation: Same as 2.1 part.
(2)有機酸の測定:有機酸の検出標準品は、3-メチル酪酸、吉草酸、キナ酸、乳酸、シュウ酸、マロン酸、安息香酸、マレイン酸、コハク酸、フマル酸、リンゴ酸、アジピン酸、酒石酸、シキミ酸、クエン酸、イソクエン酸およびL-アスコルビン酸を使用した。またアジレントのガスクロマトグラフ(GC-7890B, Agilent)を使用し、クロマトグラフィーカラムは122-5532G DB-5ms(40 m × 0.25 mm × 0.25 um)を使用し、カラム温度は270〜290℃で、仕込み口の温度は250℃で、ガス流量は0.86 mL/minであった。 (2) Measurement of organic acids: Standard products for detecting organic acids are 3-methylbutyric acid, valeric acid, quinic acid, lactic acid, oxalic acid, malonic acid, benzoic acid, maleic acid, succinic acid, fumaric acid, malic acid, Malic acid, tartaric acid, shikimic acid, citric acid, isocitrate and L-ascorbic acid were used. In addition, an Agilent gas chromatograph (GC-7890B, Agilent) was used, the chromatography column used was 122-5532 G DB-5 ms (40 m x 0.25 mm x 0.25 um), and the column temperature was 270 to 290 ° C. The mouth temperature was 250 ° C. and the gas flow rate was 0.86 mL / min.
(3)結果:測定された有機酸の収量は下記表に詳しく示す(表4)。 (3) Results: The measured yields of organic acids are detailed in the table below (Table 4).
実施例3 フィーカリバクテリウム・ロンガムFaecalibacterium longum CM04-06が生成する菌体外多糖の検出
菌体外多糖の検出はフェノール硫酸法を使用し、フェノール硫酸は遊離の単糖、オリゴ糖および多糖におけるヘキソースなどと呈色反応が発生し、出る色は吸光度に正比例し、その吸収波長は490 nmである。具体的な実験過程は以下の通りである。
Example 3 Detection of exopolysaccharide produced by Faecalibacterium longum CM04-06 The detection of exopolysaccharide uses the phenol sulphate method, and phenol sulphate is used in free monosaccharides, oligosaccharides and polysaccharides. A color reaction occurs with hexose, etc., and the color emitted is directly proportional to the absorbance, and its absorption wavelength is 490 nm. The specific experimental process is as follows.
(1)多糖の抽出
実験菌株をPYG培地(配合は実施例1と同様)で2日培養し、10mlの菌液を取って熱湯浴で30min処理した後、10000r/minで遠心し、上清を取り、最終濃度が8%になるまで80%トリクロロ酢酸を入れ、4℃で一晩処理し、タンパク質を沈殿させた。取り出して10000r/minで30min遠心し、NaOHで上清液のpHが6.0になるように調整した。2倍体積の無水エタノールを入れて多糖を沈殿させ、4℃で一晩処理し、取り出して10000r/minで30min遠心し、上清を捨て、沈殿を加熱しておいた蒸留水で溶解させた後、限外ろ過チューブ(3000Daろ過直径)に移して限外ろ過を行い、5000r/minで30min遠心し、内側のチューブに留まった多糖をメスフラスコに移して蒸留水で10mlにし、使用に備えた。
(1) Extraction of polysaccharide The experimental strain was cultured in PYG medium (formulation is the same as in Example 1) for 2 days, 10 ml of the bacterial solution was taken, treated in a boiling water bath for 30 minutes, centrifuged at 10000 r / min, and the supernatant was obtained. Was taken, 80% trichloroacetic acid was added until the final concentration was 8%, and the mixture was treated overnight at 4 ° C. to precipitate the protein. It was taken out and centrifuged at 10000 r / min for 30 minutes, and the pH of the supernatant was adjusted to 6.0 with NaOH. Twice the volume of absolute ethanol was added to precipitate the polysaccharide, treated overnight at 4 ° C, removed and centrifuged at 10000 r / min for 30 min, the supernatant was discarded and the precipitate was dissolved in heated distilled water. After that, transfer to an ultrafiltration tube (3000Da filtration diameter) for ultrafiltration, centrifuge at 5000 r / min for 30 minutes, transfer the polysaccharide remaining in the inner tube to a volumetric flask, and make 10 ml with distilled water to prepare for use. It was.
(2)グルコース標準曲線の作成
精密に標準品のグルコース20mgを100mlスフラスコに量って、目盛まで水を入れた後、それぞれ20、40、60、80、100μg/mlのグルコース標準液を調製した。各組の標準液を400μl取り、三つの平行のものを設け、順に400μlの5%のフェノールおよび1mlの濃硫酸を入れて反応させ、熱湯浴で15min反応させた後室温に冷却し、490nmにおける吸光度を測定した。その後、吸光度を縦座標とし、グルコース標準液の濃度を横座標とし、標準曲線を作成した。
(2) Preparation of glucose standard curve Precisely weigh 20 mg of standard glucose into a 100 ml flask, add water to the scale, and prepare 20, 40, 60, 80, and 100 μg / ml glucose standard solutions, respectively. .. Take 400 μl of each set of standard solution, prepare three parallel ones, add 400 μl of 5% phenol and 1 ml of concentrated sulfuric acid in order to react, react in a boiling water bath for 15 minutes, cool to room temperature, and cool at 490 nm. Absorbance was measured. Then, a standard curve was created by using the absorbance as the vertical coordinate and the concentration of the glucose standard solution as the abscissa.
(3)提出された多糖の濃度の検出
多糖溶液を400μl取り、順に400μlの5%のフェノールおよび1mlの濃硫酸を入れて反応させ、熱湯浴で15min反応させた後室温に冷却し、490nmにおける吸光度を測定した。グルコース標準曲線によって多糖の濃度を計算した。
(3) Detection of the submitted polysaccharide concentration Take 400 μl of the polysaccharide solution, add 400 μl of 5% phenol and 1 ml of concentrated sulfuric acid in order to react, react in a boiling water bath for 15 minutes, cool to room temperature, and at 490 nm. The absorbance was measured. The concentration of polysaccharide was calculated by the glucose standard curve.
(4)結果
計算したところ、2日培養されたCM04-06発酵液における菌体外多糖の含有量は233mg/Lであった。
(4) Results As a result of calculation, the content of exopolysaccharide in the CM04-06 fermented broth cultured for 2 days was 233 mg / L.
実施例4 フィーカリバクテリウム・ロンガムFaecalibacterium longum CM04-06の糖尿病動物モデルにおける体内試験
本実施例において、高脂肪飼料の投与およびストレプトゾトシン(STZ)の注射で誘導することによって2型糖尿病(T2D)モデルマウスを作り、フィーカリバクテリウム・ロンガムCM04-06を胃内投与することによって2か月治療し、CM04-06の2型糖尿病(T2D)に対する治療効果を考察した。
Example 4 In-vivo study of Faecalibacterium longum CM04-06 in a diabetic animal model In this example, a
4.1 T2Dマウスのモデル構築:試験マウスは8週齢のC57bL/6マウス(湖北医学実験動物中心から購入)を使用し、マウス試験の環境はSPF級で、適応性飼育1週間後群わけしてモデルを構築した。モデルの構築方法は高脂肪飼料とSTZで誘導し、空腹時血糖値(FBG)が10 mM/L以上になったものをT2Dモデルマウスとした。 4.1 T2D mouse model construction: Eight-week-old C57bL / 6 mice (purchased from Hubei Medical Laboratory Animal Center) were used as test mice, and the mouse test environment was SPF class. I built a model. The model was constructed by inducing with a high-fat diet and STZ, and the fasting blood glucose level (FBG) of 10 mM / L or more was used as a T2D model mouse.
4.2 実験の群分け:
(1)モデル(Model)群:T2Dモデルのマウスは生理食塩水を胃内投与した。
(2)CM04-06治療群:T2DモデルのマウスはCM04-06菌液を胃内投与して治療した。
(3)陽性薬物群:T2Dモデルのマウスは陽性薬物であるメトホルミンで関与・治療を行った。
4.2 Experiment grouping:
(1) Model group: T2D model mice were administered saline intragastrically.
(2) CM04-06 treatment group: T2D model mice were treated by intragastric administration of CM04-06 bacterial solution.
(3) Positive drug group: T2D model mice were involved and treated with the positive drug metformin.
4.3 菌液の用意:CM04-06を定常期まで培養し、菌濃度を約108cfu/mlオーダーにした。 4.3 prepared in bacterial solution: CM04-06 were cultured to stationary phase and a cell concentration of about 10 8 cfu / ml order.
4.4 試験過程:群分けの状況によって実験を行い、T2Dモデルが構築できた後(FBG>10)治療を始め、治療は2か月続いた。毎日マウスの摂食活動の様子を記録し、体重を量り、毎週尾静脈から採血し、マウスの空腹時血糖値を検出し、4週目および実験終了時マウスのブドウ糖負荷(OGTT)を測定した。2か月の試験後マウスを殺処分し、すべてのマウスは眼球を取って採血し、頸椎脱臼し、血清における総コレステロール(TC)、トリグリセリド(TG)、高密度リポタンパク質(HDL-C)および低密度リポタンパク質(LDL-C)を検出した。 4.4 Study process: Experiments were conducted according to the situation of grouping, and treatment was started after the T2D model could be constructed (FBG> 10), and the treatment lasted for 2 months. Mice's feeding activity was recorded daily, weighed, blood was drawn weekly from the tail vein, fasting blood glucose levels were detected in the mice, and glucose tolerance (OGTT) in the mice was measured at 4 weeks and at the end of the experiment. .. After a 2-month study, mice were killed, all mice were eyeballed, blood was drawn, cervical spinal dislocation, total cholesterol (TC) in serum, triglyceride (TG), high density lipoprotein (HDL-C) and Low density lipoprotein (LDL-C) was detected.
4.5 実験結果および分析
(1)体重の変化:表5および図3に示すように、試験の進行につれてマウスの体重がだんだん増加し、CM04-06およびメトホルミン治療群でマウスの体重増加の幅がモデル群よりも低かったことで、CM04-06が有効に小鼠体重の増加を緩和させることができることが示された(*P<0.05/**P<0.01)。同時に、統計によって、CM04-06がマウスの体重増加に対する制御の面でメトホルミンよりも有効であったことがわかった。
4.5 Experimental Results and Analysis (1) Changes in Body Weight: As shown in Table 5 and Figure 3, mice gradually gained weight as the study progressed, modeled on the extent of mouse weight gain in the CM04-06 and metformin-treated groups. Lower than the group, it was shown that CM04-06 could effectively mitigate the gain of small mouse weight (* P <0.05 / ** P <0.01). At the same time, statistics showed that CM04-06 was more effective than metformin in controlling mouse weight gain.
(2)CM04-06のマウスの空腹時血糖に対する実験結果 (2) Experimental results for fasting blood glucose of CM04-06 mice
表6および図4の結果から、治療の進行につれ、CM04-06およびメトホルミン群でマウスの空腹時血糖値がだんだん低下し、マウスの血糖値が正常になる傾向があり、血糖降下の効果が顕著で、CM04-06が有効に血糖を低下させることができることが示された(同モデル群の比較*P値<0.05/**P<0.01)。同時に、CM04-06群で、マウスの血糖値がメトホルミン群よりも低く、CM04-06の空腹時血糖を低下させる能力がメトホルミンよりも優れたことがわかった。 From the results in Table 6 and FIG. 4, as the treatment progressed, the fasting blood glucose level of the mice gradually decreased in the CM04-06 and the metformin group, and the blood glucose level of the mice tended to become normal, and the effect of lowering blood glucose was remarkable. It was shown that CM04-06 can effectively lower blood glucose (comparison of the same model group * P value <0.05 / ** P <0.01). At the same time, it was found that in the CM04-06 group, the blood glucose level of the mice was lower than that in the metformin group, and the ability of CM04-06 to lower the fasting blood glucose was superior to that of metformin.
(3)CM04-06のマウスの耐糖能に対する実験結果
殺処分前のマウスのブドウ糖負荷(OGTT)の状況を測定した(表7および図5)結果、ブドウ糖を胃内投与した後、30minでマウスの血糖値が最高(18.2〜22.5mmol/L)になった後、メトホルミン群とCM04-06で血糖が等速で低下し、120minで9.8 mmol/Lおよび10.1 mmol/Lになったが、モデル群でマウスの血糖は15.2で、この時点で、CM04-06血糖値がモデル群と有意差があり(*P値<0.05)、耐糖能実験の全過程を合わせてみると、比較的に、CM04-06が有効に糖尿病マウスの耐糖能低下の状況を改善することができることがわかった。ブドウ糖を調整する全過程において、CM04-06は各時点における血糖値がメトホルミンよりも低かったことで、CM04-06が糖尿病マウスの耐糖能に対する改善効果はより良いことがわかる。
(3) Experimental results on glucose tolerance of CM04-06 mice The status of glucose tolerance (OGTT) in mice before slaughter was measured (Table 7 and Fig. 5). As a result, after intragastric administration of glucose, mice were 30 min. After the highest blood glucose level (18.2 to 22.5 mmol / L), blood glucose decreased at a constant rate in the metformin group and CM04-06, reaching 9.8 mmol / L and 10.1 mmol / L in 120 min, but the model. The blood glucose of the mice in the group was 15.2, and at this point, the CM04-06 blood glucose level was significantly different from that of the model group (* P value <0.05). It was found that CM04-06 can effectively improve the condition of impaired glucose tolerance in diabetic mice. In the whole process of adjusting glucose, CM04-06 had a lower blood glucose level than metformin at each time point, indicating that CM04-06 has a better improving effect on glucose tolerance in diabetic mice.
(4)CM04-06のマウスの血中脂質に対する影響
実験終了後マウスの血中脂質を検出し、総コレステロール(TC)、トリグリセリド(TG)、低密度リポタンパク質(LDLC)および高密度リポタンパク質(HDLC)を含め、検出結果を表8に示す。結果は、メトホルミン群とCM04-06群で低密度リポタンパク質がモデル群よりも低く(*P値<0.05)、同時に、高密度リポタンパク質がモデル群よりも高く(*P値<0.05)、高密度リポタンパク質の主な機能は血液および細胞における過剰のコレステロールおよび低密度リポタンパク質を除去することで、アテローム性動脈硬化を防止する作用を有するため、CM04-06が糖尿病マウスの高脂血の症状を改善することができることがわかる。同時に、メトホルミン群に比べ、CM04-06は血中脂質に対しる改善効果がより良く、低密度リポタンパク質の含有量がより低く,高密度リポタンパク質の含有量がより高かった。
(4) Effect of CM04-06 on blood lipids in mice After the experiment was completed, blood lipids in mice were detected, and total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDLC) and high-density lipoprotein ( Table 8 shows the detection results including HDLC). The results showed that low-density lipoprotein was lower than the model group (* P value <0.05) in the metformin group and CM04-06 group, and at the same time, high-density lipoprotein was higher (* P value <0.05) and higher than the model group. CM04-06 is a symptom of hyperlipidemia in diabetic mice because the main function of density lipoprotein is to prevent atherosclerosis by removing excess cholesterol and low density lipoprotein in blood and cells. It turns out that can be improved. At the same time, CM04-06 had a better effect on blood lipids, a lower content of low-density lipoprotein, and a higher content of high-density lipoprotein than the metformin group.
実施例5 フィーカリバクテリウム・ロンガムFaecalibacterium longum CM04-06を含む食品組成物
原料の配合は表9に示す。
Example 5 Food composition containing Faecalibacterium longum CM04-06 The composition of the raw materials is shown in Table 9.
上記配合の比率で牛乳、白砂糖を混合し、完全に混合するまで撹拌し、予備加熱し、20MPaの圧力で均質化し、90℃程度で5〜10分間殺菌し、40〜43℃に冷却し、ビタミンCを混合し、1〜100×106cfu/gのFaecalibacterium longum CM04-06菌を接種し、Faecalibacterium longum CM04-06菌を含む食品組成物を調製した。 Mix milk and white sugar in the above ratio, stir until completely mixed, preheat, homogenize at a pressure of 20 MPa, sterilize at about 90 ° C for 5 to 10 minutes, and cool to 40 to 43 ° C. , Vitamin C was mixed, and 1 to 100 × 10 6 cfu / g of Faecalibacterium longum CM04-06 was inoculated to prepare a food composition containing Faecalibacterium longum CM04-06.
実施例6 フィーカリバクテリウム・ロンガムFaecalibacterium longum CM04-06を含む薬物組成物
原料の配合は表10に示す。
Example 6 The formulation of the raw material for the drug composition containing Faecalibacterium longum CM04-06 is shown in Table 10.
上記比率で乳糖、酵母粉、ペプトンおよび精製水を均一に混合し、60〜65℃に予備加熱し、20MPaの圧力で均質化し、90℃程度で20〜30分間殺菌し、36〜38℃に冷却し、ビタミンCを混合し、Faecalibacterium longum CM04-06生菌(1-50×106cfu/mL)を接種し、pH値が6.0になるまで36〜38℃で発酵させ、遠心し、水分含有量が3%未満になるまで凍結乾燥し、Faecalibacterium longum CM04-06菌の凍結乾燥物を調製した。0.5グラムのFaecalibacterium longum CM04-06凍結乾燥物を量って等量のマルトデキストリンと混合した後、カプセルに入れ、Faecalibacterium longum CM04-06菌を含む薬物組成物を調製した。
Lactose, yeast flour, peptone and purified water are uniformly mixed in the above ratio, preheated to 60-65 ° C, homogenized at a pressure of 20 MPa, sterilized at about 90 ° C for 20-30 minutes, and brought to 36-38 ° C. Cool, mix with Vitamin C, inoculate with live Faecalibacterium longum CM04-06 (1-50
実施例7 フィーカリバクテリウム・ロンガムFaecalibacterium longum CM04-06を含む薬物の調製
7.1 菌液の用意:Faecalibacterium longum CM04-06(1×109cfu/ml)を嫌気培養し、嫌気培地はPYG培地を使用し、37℃で2〜3日嫌気発酵させた。
Example 7 Preparation of drug containing Faecalibacterium longum CM04-06
7.1 Preparation of bacterial solution: Faecalibacterium longum CM04-06 (1 × 10 9 cfu / ml) was anaerobically cultured, and PYG medium was used as the anaerobic medium, and anaerobically fermented at 37 ° C. for 2 to 3 days.
7.2 成長因子の調製:脱脂牛乳、カゼインを混合し、遠心し、限外ろ過して牛乳成長因子の粗製抽出物(ビタミン類物質、プリン類物質、および/またはピリミジン類物質の栄養物質を含有する)を得た。 7.2 Growth Factor Preparation: Mix skim milk, casein, centrifuge and ultrafilter to contain crude milk growth factor extracts (vitamins, purines, and / or pyrimidines nutrients). ) Was obtained.
7.3 薬物の剤形の製造:5体積の上記成長因子を100体積のCM04-06発酵の菌液に入れ、十分に撹拌して均一に混合した後、デンプン補助剤(たとえばマルトデキストリン)を入れることによって、フィーカリバクテリウム・ロンガムFaecalibacterium longum CM04-06を含有する薬物を製造した。 7.3 Preparation of drug dosage form: Add 5 volumes of the above growth factor to 100 volumes of CM04-06 fermentation bacterial solution, stir well and mix uniformly, then add starch aid (eg maltodextrin). Produced a drug containing Faecalibacterium longum CM04-06.
菌株の寄託
本発明の菌種であるフィーカリバクテリウム・ロンガムFaecalibacterium longum CM04-06(寄託名称と同様)は、既に2016年6月13日に中国微生物菌種保蔵管理委員会普通微生物センター(CGMCC)に寄託され、住所は中国北京市朝陽区北辰西路1号院3号で、寄託番号はそれぞれCGMCC 1.5208である。
Strain Deposit Faecalibacterium longum CM04-06 (same as the deposit name), which is the strain of the present invention, has already been released on June 13, 2016 at the Ordinary Microbial Center (CGMCC) of the China Microbial Species Preservation Management Committee. ), The address is No. 3 of Hokushin West Road, Chaoyang District, Beijing, China, and the deposit number is CGMCC 1.5208.
各文献がそれぞれ単独に引用されるように、本発明に係るすべての文献は本出願で参考として引用する。また、本発明の上記の内容を読み終わった後、当業者が本発明を各種の変動や修正をすることができるが、それらの等価の形態のものは本発明の請求の範囲に含まれることが理解されるはずである。 All documents relating to the present invention are cited as references in this application, just as each document is cited independently. In addition, after reading the above contents of the present invention, those skilled in the art can make various variations and modifications to the present invention, but those equivalent forms are included in the claims of the present invention. Should be understood.
Claims (12)
ことを特徴とする組成物。 (A) Containing a safe and effective amount of Phycaribacterium longum and / or a metabolite thereof according to claim 1 and (b) a food-acceptable carrier or a pharmaceutically acceptable carrier. Characteristic composition.
前記成長因子は、ビタミン類物質、プリン類物質、ピリミジン類物質、およびこれらの組み合わせからなる群から選ばれることを特徴とする請求項3に記載の組成物。 Further look at containing the growth factor,
The composition according to claim 3, wherein the growth factor is selected from the group consisting of vitamin substances, purine substances, pyrimidine substances, and combinations thereof.
の使用であって、
(i)哺乳動物の体重増加の抑制、
(ii)哺乳動物の血中脂質レベルの低下、
(iii)哺乳動物における高密度リポタンパク質(HDL-C)のレベルの向上、
(iv)哺乳動物における低密度リポタンパク質(LDL-C)のレベルの低下、
(v)哺乳動物の血糖レベルの低下、
(vi)哺乳動物の耐糖能の向上
からなる群から選ばれる一つまたは複数の用途に使用される薬物または製剤の製造のためであることを特徴とする使用。 The use of the Phicalibacterium longum according to claim 1 or the composition according to claim 3.
(I) Suppression of mammalian weight gain,
(Ii) Decreased blood lipid levels in mammals,
(Iii) Increased levels of high-density lipoprotein (HDL-C) in mammals,
(Iv) Decreased levels of low-density lipoprotein (LDL-C) in mammals,
(V) Decreased blood glucose levels in mammals,
(Vi) Use characterized by the manufacture of a drug or formulation used for one or more uses selected from the group consisting of improved glucose tolerance in mammals.
を含むことを特徴とする請求項3に記載の組成物を製造する方法。 The composition according to claim 3 is obtained by mixing the phicalibacterium longum and / or a metabolite thereof according to claim 1 with a food-acceptable carrier or a pharmaceutically acceptable carrier. The method for producing a composition according to claim 3, further comprising a step of forming.
(b)前記培養産物からフィーカリバクテリウム・ロンガムの菌体および/またはその代謝産物を分離する工程
を含むことを特徴とする生産方法。 (A) A step of obtaining a culture product by culturing the Ficalibacterium longum according to claim 1 under appropriate culture conditions, and (b) Bacterial cells of Ficalibacterium longum from the culture product. A production method comprising the step of separating and / or its metabolites.
を含むことを特徴とする請求項11に記載の生産方法。 (C) The composition by mixing the cells of Phycaribacterium longum and / or its metabolites isolated in step (b) with a food-acceptable carrier or a pharmaceutically acceptable carrier. The production method according to claim 11, further comprising a step of manufacturing the above.
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